Methods for treatment of erectile dysfunction

ABSTRACT

Improved drug compositions and methods useful in the treatment of male erectile dysfunction. An optimized mixture of the drugs phentolamine mesylate, papaverine hydrochloride, and alprostadil in a buffer containing L-arginine and glycine is to be injected into the penile tissue to produce an erection in otherwise impotent men.

BACKGROUND OF THE INVENTION

[0001] This invention relates to improved drug compositions useful inthe treatment of male erectile dysfunction and also to methods oftreatment. More particularly, this invention discloses specificformulations containing the pharmacological agents phentolaminemesylate, papaverine hydrochloride, and alprostadil (prostaglandin E1)in a novel buffer and the administration of such formulations to mammals(including humans) to treat male impotence.

[0002] Impotence is a common medical disorder affecting about 20 millionmen in the U.S. alone. Male erectile dysfunction has been defined as theinability to achieve or maintain an erection sufficient for intercourse(Impotence, National Institutes of Health Consensus Development Panel onImpotence Conference, JAMA 1993, 270, 83-90). The dominant etiology forthis condition is arterial insufficiency associated with cardiovasculardisease. Male erectile dysfunction adversely impacts the quality oflife, being frequently associated with depression, anxiety, and lowself-esteem. Although male erectile dysfunction represents a majorclinical problem, treatment for this condition remains problematic andunsatisfactory.

[0003] One of the least invasive therapies available entails the use ofa vacuum constriction-device on the penis to produce an erection. Thephysiology of the penis is such that blood flows in through arteriesdeep within the tissue while blood flows out through veins near the skinsurface. By placing a plastic cylinder over the shaft of the penis andemploying a vacuum pump to restrict venous blood flow from the penis,the corpus cavernosum penile tissue becomes engorged with trapped bloodand an erection is produced. Common patient complaints are that thisdevice is interruptive to the sex act, has a short duration ofeffectiveness, and can cause tissue damage to the penis, such asnecrosis, with extended use.

[0004] Penile prosthesis implantation is an alternative treatment oferectile dysfunction. This therapy entails surgically implanting amechanical device inside the penis (for example see U.S. Pat. No.5,065,744 to Zumanowshky). This device can be a semi-rigid malleable rodor a fluid inflated tube which can be operated by the patient to achievean erection. Although this method does not affect the ability tourinate, ejaculate, or have an orgasm, the surgery required to implantthe prosthesis can lead to pain, infection, and scarring.

[0005] Recent insights into the physiological mechanism of penileerection have led to the development of other therapies for thetreatment of erectile dysfunction. Preliminary studies have shown thatduring sexual arousal, nitric oxide molecules are released into thesurrounding tissue from nerve endings and endothelial cells in thegenitals. These nitric oxide molecules then cause the enzyme guanylatecyclase to produce cyclic guanosine monophosphate (cGMP) which lowersthe level of intracellular calcium in the surrounding medium and allowsfor the relaxation of smooth muscle cells. In the penis, the relaxationof the corpus cavernosal smooth muscle cells permits increased bloodflow into the cavernosal spaces which leads to greater intracavernosalpressure thereby producing penile rigidity.

[0006] It follows then that a pharmacological agent which inhibits thebreakdown of cGMP would have the potential to prolong or enhance penileerections during sexual stimulation. The drug sildenafil (Viagra™,Pfizer, Inc.) is one such pharmacological agent which, when givenorally, has shown some success in this manner (Terreft, N. K. et al.Bioorg. Med. Chem. Lett. 1996, 6, 1819-1824).

[0007] Other types of oral therapies which are available to treaterectile dysfunction by different means include centrally-acting drugssuch as atipamezole (Farmos Orion) which is an α-adrenergic blocker,apomorphine (Pentech Pharmaceuticals) which is a dopaminergic agonist,and phentolamine (Vasomax™, Zonagen) which is another α-adrenergicblocker/vasodilator. This family of drugs appears to act by expandingarteries and relaxing penile tissue which, in combination, entraps bloodin the penis thereby producing an erection. However, some oral therapiesmay have drawbacks with respect to efficacy and side effects. Therefore,in those cases it would be beneficial to treat impotence directly byadministering medicaments directly on/into the penis itself. These modesof administration may also minimize the dosage of the medicament needed.

[0008] One alternative route for administering vasoactive agents likethose mentioned above is by transdermal administration to the penis. Thecompound alprostadil (prostaglandin E1) is formulated as a cream(Macrochem) which is absorbed into the penile tissue. Alprostadil hasbeen shown to bind to specific receptors in penile tissue which isaccompanied by an increase in cellular cyclic adenosine monophosphate(cAMP) levels. The physiological mechanism, as described with cGMPabove, results in a decrease of intracellular calcium in the cytoplasmand the relaxation of smooth muscle cells. These vasodilatory effectsresult in rapid arterial inflow and expansion of the sinusoidal spaceswithin the penis. This action then restricts venous outflow from thepenis whereby penile rigidity develops. Another vasoactive agent,papaverine hydrochloride, is formulated into a patch (PharmaPatch,Pharmedia) to be applied to the skin of the penis and acts as anon-specific phosphodiesterase inhibitor to maintain cGMP levels in asimilar sort of mechanism as described above which produces an erection.These external treatments of the skin surface of the penis suffer fromthe drawback that the sex partner comes into contact with the drugduring intercourse and can be adversely affected.

[0009] The above-mentioned pharmacological agents and routes ofadministration represent therapies for the treatment of erectiledysfunction which can be successful for about 75-80% of the 20 millionmen having erectile dysfunction. However, for the remaining impotentpopulation, a different treatment is needed which often includesintraurethral and/or intracavernosal injection therapy.

[0010] Currently, there are two FDA-approved injection therapiesavailable (Caverject®, Pharmacia-Upjohn; and Edex™, Schwartz Pharma),both of which employ alprostadil as the active component. Caverject® iscommercially marketed as a freeze-dried powder containing the activeingredient alprostadil in a base of lactose, sodium citrate, and benzylalcohol. When reconstituted with water, Caverject® is injected into theintracavernosal space of the penis. Similarly, EDEX™ is a lyophilizedpowder containing alprostadil, α-cyclodextrin, and anhydrous lactose. Itis also reconstituted with water before injection into theintracavernosal space of the penis. A urethral suppository ofalprostadil (MUSE™, Vivus, Inc.) has also recently been introduced intothe market; however, it has shown disappointing clinical results(Biotech. Newswatch, Jun. 15, 1998, 4-5). Not all impotent men respondto alprostadil therapy alone.

[0011] In order to treat these individuals who were non-responsive toalprostadil, Zorgniofti et al. (J. Urol. 133:39-41 (1985), incorporatedherein by reference) demonstrated that the intracavernosal injection ofa combination of papaverine hydrochloride and phentolamine mesylaterapidly produced transitory penile tumescence which could be followed byan erection in response to sexual stimulation.

[0012] Similarly, Althof et al. (J. Sex Marital Ther. 17(2):101-112(1991), incorporated herein by reference) reported that intracavernosalinjection of papaverine hydrochloride and phentolamine mesylate resultedin improved erectile ability in about 84% of patients injected. However,there was a high dropout rate (57%) in this study because 25% ofpatients developed fibrotic nodules, 30% had abnormal liver functions,and 19% experienced bruising of the penile tissue. In another studyusing the same combination of phentolamine mesylate and papaverinehydrochloride, the intracavernous injection of this combination led tomarked penile fibrosis in the patients injected (see Larsen, E. K. etal. J. Urol. 137, 292-293 (1987) incorporated herein by reference).

[0013] Therefore, a need exists for a safe and effective alternativetreatment for impotence which minimizes the drawbacks of the therapiesdescribed above to those currently available.

SUMMARY OF THE INVENTION

[0014] Compositions and methods for the treatment of male erectiledysfunction are provided. When injected into the corpus cavernosum, thecompositions of this invention aid in producing, enhancing, orsustaining an erection of the penis. The compositions comprise one ormore of the following pharmaceutically active agents: an α-adrenergicblocker, a phosphodiesterase inhibitor, and a prostaglandin. Preferredα-adrenergic blockers include phentolamine mesylate and phentolaminehydrochloride. Preferred phosphodiesterase inhibitors include papaverinehydrochloride, Sildenifil (Pfizer). Preferred prostaglandins includealprostadil, any pharmaceutically acceptable salts, hydrates,hemihydrates, ester or other pharmaceutically acceptable forms of theforegoing pharmaceutically active agents are also included within thescope of the invention. Other Class V phosphodiesterase inhibitors arealso preferred. A preferred composition is a trimix comprisingphentolamine mesylate, alprostadil and papaverine hydrochloride.Preferably, the trimix further comprises a buffer which buffer comprisesa substrate for nitric oxide synthetase. A preferred substrate isarginine.

[0015] Preferred buffers include one or more substrates for nitric oxidesynthetase. More preferred buffers comprise glycine, arginine, ormixtures thereof. Even more preferably, the buffer comprises a mixtureof glycine, L-arginine, mannitol, and benzyl alcohol in water. Theforegoing buffers may also comprise other pharmaceutical excipientcarriers and the like. The advantages to the use of these buffer inconjunction with the mentioned active agents include improved solubilityprofiles of the pharmaceutical agents and they provide substrates forthe enzyme nitric oxide synthetase, which has been shown to play a rolein the erectile response, and may result in a lower dosage requirementfor efficacy.

DETAILED DESCRIPTION OF THE INVENTION

[0016] The present invention is directed to improved compositions which,by way of a non-limiting example, comprise the vasoactive agentsphentolamine mesylate, papaverine hydrochloride, and alprostadil (or anypharmaceutically acceptable salts of these vasoactive agents). Anotheraspect of the invention is directed to compositions comprising one ormore vasoactive agents such as papaverine, phentolamine, and alprostadilin a buffer comprising either glycine, L-arginine, or a mixture ofglycine and L-arginine. By virtue of the improved solubility profiles ofthe vasoactive agents in the buffers of the present invention, the useof the inventive compositions lowers the incidence of fibrotic nodulesin the penis and priaprism caused by precipitation and depot formationof vasoactive agents at the site of injection. Without being bound bytheory, it is also believed that the presence of L-arginine in thecompositions of the invention or other substrates for nitric oxidesynthetase may lower the effective dosage of the vasoactive agents inthe compositions.

[0017] When compositions according to the present invention compriseonly an α-adrenergic blocker or a phosphodiesterase inhibitor or aprostaglandin as the pharmaceutically active agent, the composition willfurther comprise a buffer which buffer comprises a substrate for nitricoxide synthetase such as arginine. When the compositions of theinvention comprise two or more of the pharmaceutically active agentsdescribed above, the compositions optionally comprise buffers whichcomprise a substrate for nitric oxide synthetase.

[0018] Particularly preferred for the present purposes is a compositioncomprising an α-adrenergic blocker (e.g., phentolamine mesylate), aphosphodiesterase inhibitor (e.g., papaverine hydrochloride orSildenifil), and a prostaglandin (e.g., alprostadil) in a buffer. Theactive ingredients phentolamine mesylate, papaverine hydrochloride, andalprostadil are present in the composition in a weight ratio in therange of about 0.5:7.5:0.005 to about 5:30:0.02. More preferably, theweight ratio of phentolamine mesylate: papaverine hydrochloride:alprostadil is about 1:30:0.01.

[0019] Dosages of the vasoactive components of the invention are in therange of about 0-40 μg/ml alprostadil, about 0-50 mg/ml papaverine, andabout 0-10 mg/ml phentolamine in a total volume of about 0.5 ml.Preferred dosages of the inventive compositions are in the range ofabout 1.25-5 mg/ml phentolamine, about 7.5-30 mg/ml papaverine, andabout 5-20 μg/ml alprostadil in a total volume of about 0.5 ml. Morepreferably, the dose is about 1 mg/ml phentolamine, about 30 mg/mlpapaverine, and about 0.01 mg/ml alprostadil in a total volume of about0.5 ml.

[0020] In the case of a composition of the invention containing onlyphentolamine as the vasoactive agent in combination with a buffer suchas an arginine and/or glycine containing buffer, the preferred dosage isabout 1.25 mg/ml in a total volume of 0.5 ml. For a compositioncontaining only papaverine in combination with an arginine and/orglycine contains buffer as the vasoactive agent, the preferred dosage isabout 7.5 mg/ml in a total volume of 0.5 ml. In a composition containingonly alprostadil as the vasoactive agent in an arginine and/or glycinecontaining buffer, the preferred dosage is about 5 μg/ml in a totalvolume of 0.5 ml. Compositions comprising only two of the vasoactiveagents in a buffer according to the present invention are alsocontemplated by the invention.

[0021] The active ingredients are administered in a buffer whichenhances their solubility and/or provides a substrate for nitric oxidesynthetase. The buffer preferably contains glycine, mannitol, and benzylalcohol in water. In this buffer, the content of glycine is preferablyin the range of about 1% to about 2% by weight. More preferably, thebuffer contains L-arginine, glycine, and other pharmaceuticallyacceptable excipients such as mannitol, and benzyl alcohol in water. Theweight ratio of L-arginine to glycine in this preferred buffer is about1:20. The pH of the composition in buffer is from about 3 to about 7. Apreferred pH range for the composition is from about 3 to about 5.

[0022] Also included in the present inventions is a method for thetreatment of male erectile dysfunction which comprises administering apharmacologically effective amount of a composition comprising anα-adrenergic blocker, a phosphodiesterase inhibitor, and aprostaglandin. Preferably, in this method the composition comprisesphentolamine mesylate, papaverine hydrochloride, and alprostadil in abuffer. In this method of treatment, the route of administration is amember of the group consisting of oral, transdermal, subcutaneousintraperitoneal, intramuscular, and intrapenile (includingintracavernosal). A preferred route of administration if byintracavernosal injection.

[0023] The composition utilized in this method of treatment preferablycomprises phentolamine mesylate, papaverine hydrochloride, andalprostadil in a weight ratio in the range of about 0.5:7.5:0.005 toabout 5:30:0.02. More preferably, phentolamine mesylate, papaverinehydrochloride, and alprostadil are present in the composition in aweight ratio of about 1:30:0.01.

[0024] Dosages of the vasoactive agents useful in this method oftreatment are in the range of about 0-40 μg/ml alprostadil, about 0-50mg/ml papaverine, and about 0-10 mg/ml phentolamine in a total volume ofabout 0.5 ml. Preferred dosages of the vasoactive agents are in therange of about 1.25-5 mg/ml phentolamine, about 7.5-30 mg/ml papaverine,and about 5-20 μg/ml alprostadil in a total volume of about 0.5 ml. Morepreferably, the dose in this method is about 1 mg/ml phentolamine, about30 mg/ml papaverine, and about 0.01 mg/ml alprostadil in a total volumeof about 0.5 ml.

[0025] Methods utilizing a composition containing only phentolamine asthe vasoactive agent, the preferred dosage rate is about 1.25 mg/ml in atotal volume of 0.5 ml. For a method utilizing a composition containingonly papaverine as the vasoactive agent, the preferred dosage rate isabout 7.5 mg/ml in a total volume of 0.5 ml. In a method using acomposition containing only alprostadil as the vasoactive agent, thepreferred dosage rate is about 5 μg/ml in a total volume of 0.5 ml.

[0026] The buffer used to solubilize the active ingredients in theforegoing methods comprise mixtures of glycine, mannitol, and benzylalcohol in water. The glycine content of this buffer is preferably inthe range of about 1% to about 2% by weight. More preferably, the buffercomprises a mixture of glycine, L-arginine, mannitol, and benzyl alcoholin water. The weight ratio of glycine to L-arginine in the preferredbuffer is about 1:20. The pH of the composition of the invention in thebuffer is from about 3 to about 7. Preferred is a pH from about 3 toabout 5.

[0027] The present invention is further illustrated by the followingexamples which assess the increased solubility of the active ingredientsphentolamine, papaverine, and alprostadil in a buffer comprising glycineand arginine and also the ability of the improved compositions to inducepenile erection in rabbits upon the intracavernosal injection of thecomposition containing phentolamine mesylate, papaverine hydrochloride,and alp^(SM)rostadil in buffer at various pH. The use of the compositionof the present invention for treatment of impotence in humans is alsoprovided.

[0028] The foregoing specification and Examples are intended toillustrate the present invention and are intended to limit the scope ofthe invention as set out in the appended claims.

EXAMPLE 1 Solubility of Phentolamine-Papaverine in Glycine-ArginineBuffer at Various pH

[0029] Papaverine is sparingly soluble (<1 mg/ml) in the presence ofphentolamine at physiological pH. Under these conditions papaverine mayprecipitate producing a deposit of solid drug at the injection site.This deposit of solid papaverine could act as a depot of drug whichcontinues to exert its effects on erectile ability over time increasingthe risk for priaprism and the occurrence of nodules/fibrosis in thepenis.

[0030] In order to address this problem, the buffers at the injectionsite comprising glycine, arginine, or a mixture of glycine andL-arginine were prepared in an attempt to promote the solubility of theactive ingredients papaverine and phentolamine and to provide substratefor nitric oxide synthetase. A series of saturated solutions containingthe pharmaceutically active ingredients in buffer at various pH wereprepared, filtered, then analyzed by a high performance liquidchromatograph (HPLC) with an ultra-violet wavelength detector todetermine the concentration of the dissolved phentolamine and papaverineactive ingredients.

[0031] Saturated solutions of papaverine hydrochloride and solidphentolamine mesylate at a constant ratio of about 6 to about 1 wereadded in the amounts indicated in Table 1 to buffer containing about 0.1M glycine and about 2 mM L-arginine, initial pH 8.2. A 0.1 N solution ofNaOH was used to adjust the pH to the indicated values. These solutionswere shaken for about 10 minutes then held at room temperature overnightin order to allow maximum dissolution of drugs in the buffer. Thesamples were then filtered through a 0.45 μl PFTE filter to removeundissolved drug and analyzed by high pressure liquid chromatography(HPLC) to determine how much of each drug went into solution as thevarious pH values. HPLC was performed using a C18 column having a mobilephase of buffer (5 mM NaH₂PO₄ and 5 mM octane sulfonic acid, pH 3) in30% acetonitrile with a flow rate of 1.5 ml/minute. The detectionwavelength was 210 nm. Standard curves of both phentolamine andpapaverine were prepared in order to determine the concentration of thephentolamine-papaverine mixtures in the samples by measurement of peakarea. TABLE 1 Solubility of Papaverine Hydrochloride and PhentolamineMesylate in a Mixture vs. pH in buffer of 0.1 M glycine and 2 mMArginine Papaverine (mg/ml) Phentolamine (mg/ml) pH Added to Buffer InSolution Added to Buffer In Solution 3.91 66 36.81 11 12.12 4.35 60 7.7510 9.88 5.04 60 0.7 10 6.5 7.48 60 0.17 10 4.97 7.65 60 0.2 10 6.99

[0032] The data demonstrates that for papaverine the solubility wasabout 36.81 g/ml in the glycine-arginine buffer at pH 3.91. In contrast,in a glycine-arginine buffer of pH 7.48 the solubility was only about0.2 mg/ml. Therefore, the use of a buffer containing glycine andL-arginine at a pH of about 3-5 enhances the solubility of papaverine incontrast to a buffer having a pH greater than 7.0. Similarly, thesolubility of phentolamine in the mixture was, in general, greater atlower pH. However; at pH 7.65 an increase in solubility of phentolaminewas seen. The increased solubility of the vasoactive drugs in thebuffers of the present invention reduces the possibility that the drugswill form depots at the site of invention.

EXAMPLE 2 Intracavernosal Injection of Trimix Formulations

[0033] Four New Zealand white rabbits were utilized in this study todetermine the effects of the intracavernosal injection of twoformulations of the compositions of the present invention. Thecompositions comprised a trimix of alprostadil, phentolamine mesylateand papaverine hydrochloride. The detailed compositions are listed inTable 2 below. The content formulations of A and B are similar exceptthat formulation B contains no L-arginine. TABLE 2 Composition ofInjectable Trimix Formulations Formulation A (per ml) Formulation B (perml) Alprostadil   20 μg  20 μg Phentolamine   5 mg   5 mg MesylatePapaverine HCl   30 mg  30 mg L-Arginine 0.35 mg None Glycine  7.5 mg7.5 mg Mannitol   24 mg  24 mg Benzyl alcohol  8.4 mg 8.4 mg Final pH:3.98 Final pH: 4.01 Sterile filtered Sterile filtered

[0034] Two of the rabbits underwent intracavernosal injections ofsolution A and the other two rabbits underwent intracavernosalinjections of solution B. In preparation for these injections, therabbits were anesthetized by intramuscular injection of ketamine (35mg/kg) and xylazine (5 mg/kg). Anesthesia was maintained with 0.2 mlintravenous bolus injections of pentobarbital (25 mg/ml) as needed. A 20gauge angiocatheter was placed into the carotid artery for on-linemeasurement of systemic arterial pressure. A 23 gauge mini-catheter wasplaced intracavernosally for measurement of intracavernosal pressureduring erection. Baseline arterial blood pressure and intracavernosalpressure were recorded. Once baseline had been established, 0.2 ml ofeither solution A or solution B was injected intracavernosally. Theeffects of intracavernosal drug administration on intracavernosalpressure and systemic arterial pressure were continuously recorded.Further intracavernosal injections were made if full penile erection wasnot produced.

[0035] The results indicate that the first rabbit given anintracavernosal injection of 0.2 ml of solution A experienced a fullpenile erection lasting more than 30 minutes. The intracavernosalpressure, a measurement of engorgement, increased from about 30 mm Hg toabout 63 mm Hg (91% of mean systemic arterial pressure after injection).The only side effect noted was a minor hypotension event lasting forapproximately 10 seconds. There was no effect on heart rate.

[0036] The second rabbit given an intracavernosal injection of 0.2 ml ofsolution A also experienced a full penile erection lasting about 4minutes. The intracavernosal pressure after injection rose from about 35mm Hg to about 69 mm Hg (83% of mean systemic arterial pressure). Thisrabbit was injected intracavernosally a second time with 0.2 ml ofsolution A which produced another full penile erection lasting more than30 minutes. After the second intracavernosal injection, theintracavernosal pressure increased from about 28 mm to about 65 mm Hg(96% of mean systemic arterial pressure). The only side effect noted wasa minor transient hypotension which lasted for about 8 seconds. Therewas no effect on heart rate.

[0037] The third rabbit received an intracavernosal injection of 0.2 mlof solution B which produced a partial erection lasting for 3 minutes.The first injection increased intracavernosal pressure from about 36 mmHg to about 50 mm Hg (60% of mean systemic arterial pressure). Thesecond injection produced a full penile erection lasting for over 30minutes. After the second intracavernosal injection, intracavernosalpressure increased from about 28 mm Hg to about 65 mm Hg (96% of meansystemic arterial pressure). The only side effect noted was a minortransient hypotension lasting for approximately 6 seconds. There was noeffect on heart rate.

[0038] The fourth rabbit received two injections, each 0.2 ml ofsolution B which failed to produce an erection and caused only a minorincrease in intracavernosal pressure from about 15 mm Hg to about 33 mmHg. A third injection of 0.2 ml of solution B produced a partialerection increasing intracavernosal pressure from about 30 mm Hg toabout 45 mm Hg (64% of mean systemic arterial pressure). A fourthinjection of 0.2 ml of solution B caused a full penile erection lastingfor about 15 minutes. After the fourth injection the intracavernosalpressure increased from 42 mm Hg to about 65 mm Hg (88% of systemicarterial pressure). After every injection a transient minor hypotensionlasting for 5-8 seconds was observed. There was no change in heart rate.

[0039] These experiments demonstrate that the intracavernosaladministration of solution A or solution B produced penile erection inthe rabbit. Erectile response to solution A occurred after one injectionin the first rabbit and after two injections in the second animal.Erectile response to solution B occurred after two injections in thefirst animal and after four injections in the second animal. Therefore,it appears that both solutions A and B containing the active ingredientsphentolamine mesylate, papaverine hydrochloride, and alprostadil inbuffers of either glycine or glycine-arginine provide effectivetreatment of male erectile dysfunction; however, the number ofinjections needed to produce an erection in the rabbit was less usingsolution A than solution B. Solution A containing L-arginine appearsthen to be more effective as an impotence therapy than solution B. Theinvention also contemplates the use of one or more of each of theforegoing vasoactive agents in buffers containing substrates for nitricacid synthetase. As described above, preferred buffers include glycineand arginine and pharmaceutically acceptable excipients and/or carriers.

EXAMPLE 3 Treatment of Impotence in Humans

[0040] Although the foregoing examples described the effect of a trimixof alprostadil, phentolamine mesylate, and papaverine hydrochloride inbuffers with or without arginine on erectile function in rabbits,dosages for administration to humans of vasoactive agents in thecompositions of the present invention may be ready determined by one ofordinary skill in the art. For example, appropriate base-line dosagesmay be determined by reference to Zorgniotti, et al. (J. Urol.133:39-41, 1985) who demonstrated that intracavernosal injection of 30mg of papaverine in combination with 0.5 to 1 mg phentolamine (totalvolume of one ml) produced penile erection in response to sexualstimulation.

[0041] Dosages of the vasoactive agents useful in the compositions andmethods of the present invention are in the range of about 0.5 to about40 μg/ml alprostadil, about 0.5 to about 50 mg/ml papaverine, and about0.5 to about 10 mg/ml phentolamine in a total volume of about 0.5 ml.Preferred dosages of the inventive compositions are in the range ofabout 1.25-5 mg/ml phentolamine, about 7.5-30 mg/ml papaverine, andabout 5-20 μg/ml alprostadil in a total volume of about 0.5 ml. Morepreferably, the dose in this method is about 1 mg/ml phentolamine, about30 mg/ml papaverine, and about 0.01 mg/ml alprostadil in a total volumeof about 0.5 ml. Erectile response may be measured by any of severalcriteria well known in the art.

[0042] According to the invention, the use of arginine or othersubstrates for nitric oxide synthesis in combination with vasoactivesubstances including phentolamine and/or alprostadil and/or papaverinemay enhance or restore sexual response or responsiveness in impotent menwhen compared to the composition without arginine or other nitric acidsynthetase substrates. The presence of arginine or other nitric oxidesynthetase substrates may also allow the use of smaller dosages of thevasoactive agents resulting in a more cost-effective therapy, with fewerside effects.

[0043] The foregoing specification is intended to illustrate the presentinvention but is not intended to limit the invention as set out in theappended claims. Still other variations within the spirit and scope ofthe present invention are possible and will readily present themselvesto those skilled in the art.

We claim:
 1. A composition comprising one or more pharmaceutical agentsselected from the group consisting of an α-adrenergic blocker, aphosphodiesterase inhibitor, and a prostaglandin in a buffer whereinsaid buffer comprises a substrate for nitric acid synthetase.
 2. Thecomposition of claim 1 wherein the α-adrenergic blocker is phentolaminemesylate, or any pharmaceutically acceptable salt thereof.
 3. Thecomposition of claim 1 wherein the phosphodiesterase inhibitor isselected from the group consisting of papaverine hydrochloride orSildenafil or any pharmaceutically acceptable salt thereof.
 4. Thecomposition of claim 1 wherein the prostaglandin is alprostadil.
 5. Thecomposition of claim 1 wherein the buffer comprises L-arginine and,optionally, a pharmaceutically acceptable excipient or carrier.
 6. Thecomposition of claim 5 wherein the buffer comprises glycine having a pHrange of from about 3 to about
 5. 7. The composition of claim 1 whereinthe buffer comprises a mixture of arginine and glycine having a pH rangeof from about 3 to about
 5. 8. The composition of claim 1 wherein thebuffer comprises glycine and L-arginine in a weight ratio of about 1:20.9. The composition of claim 7 wherein the buffer further comprisesbenzyl alcohol and mannitol and has a pH range of from about 3 to about5.
 10. The composition of claim 1 wherein the weight ratio ofphentolamine mesylate: papaverine hydrochloride: alprostadil is about0.5:7.5:0.005 to about 5:30:0.02.
 11. The composition of claim 1 whereinthe weight ratio of phentolamine mesylate:papaverinehydrochloride:alprostadil is about 1:30:0.01.
 12. The composition ofclaim 1 wherein the dosage of phentolamine mesylate, papaverinehydrochloride, and alprostadil are in the range of about 0-40 μg/mlalprostadil, about 0-50 mg/ml papaverine, and about 0-10 mg/mlphentolamine.
 13. The composition of claim 1 wherein the dosage ofphentolamine mesylate, papaverine hydrochloride, and alprostadil are inthe range of about 1.25-5 mg/ml phentolamine, about 7.5-30 mg/mlpapaverine, and about 5-20 μg/ml alprostadil.
 14. The composition ofclaim 1 wherein the dosage of phentolamine mesylate, papaverinehydrochloride, and alprostadil are about 1 mg/ml phentolamine, about 30mg/ml papaverine, and about 0.01 mg/ml alprostadil.
 15. The compositionof claims 12, 13, or 14 wherein the vasoactive agents are present in atotal volume of 0.5 μl.
 16. The composition of claim 1 wherein thedosage of alprostadil is about 5 μg/ml in a total volume of 0.5 ml. 17.The composition of claim 1 wherein the dosage of phentolamine is about1.25 mg/ml in a total volume of 0.5 ml.
 18. The composition of claim 1wherein the pH range of the buffer is from about 3 to about
 7. 19. Amethod for the treatment of male erectile dysfunction which comprisesadministering a pharmacologically effective amount of a compositioncomprising one or more of the following pharmaceutical agents selectedfrom the group consisting of an α-adrenergic blocker, aphosphodiesterase inhibitor, and a prostaglandin in a buffer.
 20. Themethod of claim 19 wherein the α-adrenergic blocker is phentolaminemesylate, or any pharmaceutically acceptable salt thereof.
 21. Themethod of claim 19 wherein the phosphodiesterase inhibitor is papaverinehydrochloride or any pharmaceutically acceptable salt thereof.
 22. Themethod of claim 19 wherein the prostaglandin is alprostadil.
 23. Themethod of claim 19 wherein the buffer comprises L-arginine and,optionally, a pharmaceutically acceptable excipient or carrier.
 24. Themethod of claim 23 wherein the buffer comprises glycine having a pHrange of from about 3 to about
 5. 25. The method of claim 19 wherein thebuffer comprises a mixture of arginine and glycine having a pH range offrom about 3 to about
 5. 26. The method of claim 19 wherein the buffercomprises glycine and L-arginine in a weight ratio of about 1:20. 27.The method of claim 25 wherein the buffer further comprises benzylalcohol and mannitol and has a pH range of from about 3 to about
 5. 28.The method of claim 19 wherein the weight ratio of phentolaminemesylate: papaverine hydrochloride: alprostadil is about 0.5:7.5:0.005to about 5:30:0.02.
 29. The method of claim 19 wherein the weight ratioof phentolamine mesylate: papaverine hydrochloride: alprostadil is about1:30:0.01.
 30. The method of claim 19 wherein the dosage of phentolaminemesylate, papaverine hydrochloride, and alprostadil are in the range ofabout 0-40 μg/ml alprostadil, about 0-50 mg/ml papaverine, and about0-10 mg/ml phentolamine.
 31. The method of claim 19 wherein the dosageof phentolamine mesylate, papaverine hydrochloride, and alprostadil arein the range of about 1.25-5 mg/ml phentolamine, about 7.5-30 mg/mlpapaverine, and about 5-20 μg/ml alprostadil.
 32. The method of claim 19wherein the dosage of phentolamine mesylate, papaverine hydrochloride,and alprostadil are about 1 mg/ml phentolamine, about 30 mg/mlpapaverine, and about 0.01 mg/ml alprostadil.
 33. The method of claim30, 31, or 32 wherein the vasoactive agents are present in a totalvolume of 0.5 μl.
 34. The method of claim 19 wherein the dosage ofalprostadil is about 5 μg/ml in a total volume of 0.5 ml.
 35. The methodof claim 19 wherein the dosage of phentolamine is about 1.25 mg/ml in atotal volume of 0.5 ml.
 36. The method of claim 19 wherein the pH rangeof the buffer is from about 3 to about
 7. 37. A composition comprisingan α-adrenergic blocking agent, a phosphodiesterase inhibitor and aprostaglandin in a pharmaceutically acceptable carrier or excipient. 38.The composition of claim 37 wherein the α-adrenergic blocking agent isphentolamine or a pharmaceutically acceptable salt thereof.
 39. Thecomposition of claim 37 wherein the phosphodiesterase inhibitor isselected from the group consisting of Sildenafil and papaverine orpharmaceutically acceptable salts thereof.
 40. The composition of claim37 wherein the prostaglandin is alprostidil.
 41. The compositionaccording to claim 37, 38, 39, and 40 further comprising a buffer. 42.The composition according to claim 41 wherein the buffer comprisesglycine, arginine, or a mixture thereof.
 43. The composition accordingto claim 41 wherein the composition has a pH range from about 3 to about7.
 44. The composition according to claim 41 wherein the composition hasa pH range from about 3 to about
 5. 45. The composition according toclaim 42 wherein the composition has a pH range from about 3 to about 7.46. The composition according to claim 42 wherein the composition has apH range from about 3 to about 5.